Phase III Single-Blinded Study Of Pemetrexed + Cisplatin Vs. Cisplatin Alone In Chemonaive Patients With Malignant Pleural Mesothelioma
|
Nicholas J. Vogelzang, MD, with comments by Valerie W. Rusch, MD. (Transcribed from MARF Executive Director Chris Hahn's notes of the presentation made at the plenary session of ASCO, May 20, 2002.)
In one of just four abstracts presented before the entire ASCO conference, Dr. Vogelzang (head of the University of Chicago Cancer Research Center and member of MARF's Board of Directors) presented the results of this Phase III study comparing pemetrexed plus cisplatin to cisplatin alone. According to Dr. Vogelzang: With 473 patients randomized (i.e satisfying the eligibility criteria and randomly selected to begin either arm of the study), this was the largest phase III clinical trial ever conducted in mesothelioma. Pemetrexed is an antifolate. It is transported across the cell membrane; it then inhibits three key enzymes all necessary for DNA and RNA synthesis. The basis for conducting the clinical trial was evidence that pemetrexed had a 14% response rate in malignant mesothelioma (mm) in earlier studies, similar to that of other antifolates, and that like other antifolates, it appeared more active in phase I and II studies in combination with other platinum analogues. (Pemetrexed and cisplatin in combination had shown a 45% response rate, pemetrexed and carboplatin 32%, and raltitrexed and oxaliplatin 25%). Therefore, in 1998 Dr. Vogelzang and his colleagues designed a clinical trial to determine whether pemetrexed plus cisplatin was more effective in mm than cisplatin alone. The goal was to accrue 280 patients. These would be stratified and randomized between the two arms of the study by recognized prognostic factors, including performance status, gender, white blood cell count, histology and disease measurability. The primary endpoint of the study would be survival; secondary endpoints would include time to progressive disease, tumor response rate, toxicity, pulmonary function, and a modified lung cancer symptom scale. Eligibility criteria for the study included diagnosis of pleural malignant mesothelioma, no prior chemotherapy, and not a candidate for surgery. The dose was 500 mg/m2 pemetrexed intravenous over 10 minutes, followed 30 minutes later by 75 mg/m2 cisplatin intravenous over two hours on day one every three weeks, versus the exact same cisplatin dose without pemetrexed. Soon after the trial began, there were 3 deaths (7% of the first 43 patients in the pemetrexed/cisplatin arm) versus only 1 death in the cisplatin arm. Symptoms were febrile neutropenia and diarrhea. Both of these symptoms were linked to elevated baseline levels of homocysteine, which correlates to folic acid deficiency. The symptom of diarrhea alone was linked to vitamin B12 deficiency. Therefore, for patient safety, beginning on December 2, 1999, low dose folic acid and B12 supplementation was required in all study participants, including those who had already begun treatment, beginning 7 to 21 days prior to, and continuing through, drug treatment. To be included in the final analysis of the study, each patient had to have received at least one dose of whichever study drug they were randomized to. This ultimately included 448 patients. Follow-up on each of these patient was conducted for at least 9 months from randomization, and the study was then considered mature. At that time, 304 of the 448 patients had died. Of the 448 final analysis patients, 70 were in the group that had never been supplemented, 47 patients were partially supplemented (i.e. they began the trial before supplementation began and continued in it thereafter), and 331 patients were fully supplemented. The baseline characteristics of this entire group were well balanced between the two arms of the study. For example, 8% of the pemetrexed/cisplatin patients had sarcomatoid histology, versus 11% in the cisplatin arm. Clinical stage between the two arms was also the same. Results were as follows: Among the entire group, mean survival time was 9.3 months in the cisplatin only arm, versus 12.1 months in the pemetrexed/cisplatin arm. This difference is highly statistically significant. Among just the fully supplemented group, mean survival time was 10 months versus 13.3 months. Time to progression in the entire group was 3.9 months versus 5.7 months. Among the fully supplemented group, time to progression was 3.9 months versus 6.1 months. Again, this difference is highly statistically significant. Tumor response rate in the entire group was 17% versus 41%. In the fully supplemented group tumor response rate was 20% versus 46%. Among those who were only partially or never supplemented, tumor response rate was 9% versus 29%. All of these differences are highly statistically significant. Response was defined as at least a 30% reduction in pleural rind thickness using a new, objective spiral CT scan measuring method. The superior results in the fully supplemented group over the partially or not supplemented groups in the pemetrexed/cisplatin arm were probably due to less toxicity. With supplementation, patients were able to complete more cycles and thus obtain more benefit. These superior results with regard to median survival time and tumor response rate in the cisplatin only arm indicate that supplementation appears beneficial as well where treatment is cisplatin alone. The median number of cycles the pemetrexed/cisplatin patients were able to undergo increased from 2 in the never supplemented group to 6 in the fully supplemented group. Interestingly, the cisplatin only group had nearly the same increase. As expected, grade toxicity was more common in the pemetrexed/cisplatin arm: Drug related death was 4% versus 2%, neutropenia 28% versus 2%. Supplementation significantly reduced side effects in the pemetrexed/cisplatin arm: drug related death went from 7% in the never supplemented group to 3% in the fully supplemented group, and neutropenia went from 41% to 23%. Lung function in the pemetrexed/cisplatin patients began to improve in the second cycle and continued to improve compared to the cisplatin alone patients throughout the six cycles. Dyspnea improved correspondingly. Beginning also with the second cycle, pain became less in the pemetrexed/cisplatin patients than in the cisplatin alone patients, and thereafter became significantly less. The conclusions from the study are:
Dr. Vogelzang closed by thanking the 114 investigators in 19 countries who participated in conducting the study, and the Eli Lilly company, "which so boldly supported this vital work." Dr. Valerie Rusch commented on Dr. Vogelzang's presentation of the study: Mesothelioma is an uncommon disease, affecting two to three thousand patients annually in the U.S, with an incidence expected to increase world-wide until 2020. It is usually fatal. Its pathogenesis and tumor biology are poorly understood. It has been surrounded with an attitude of extreme nihilism. However, there have been advances in the last ten years. These include acceptance of a uniform, international staging system, decreased surgical mortality, much better understanding of the disease's natural history, and somewhat better understanding of the tumor's biology. Until recently, studies of chemotherapy in mesothelioma have usually been only phase II studies which used drugs already approved for other cancers, and which were not well designed. Important features of this pemetrexed clinical study include: It was a large, international phase III, which accommodates the heterogeneous nature of the tumor. It included a method of carefully measuring response rates, originally proposed by doctors Byrne and Robinson of Australia. The study is relevant to typical patients. The patients included in the study were not "selected" but were absolutely typical. The results of the cisplatin alone arm were entirely consistent with results from other studies, showing that this study group was not a better prognosis group than in other studies. This was a "real world" study group. The conclusions to be drawn from the study are:
The study raises a number of questions and future study areas for the future:
|